The growing interest in chronic kidney disease (CKD) has shed light on the striking incidence of cardiovascular disease (CVD) comorbidity that is characteristic of all stages of this illness. It is clear that patients who have CKD, regardless of age, race, or gender, suffer from a 10- to 100-fold greater incidence of death from CVD than their counterparts in the general population.^[1] This scourge is present most notably for those patients with kidney failure receiving renal replacement therapy, but also for persons with earlier stages of CKD or recipients of a kidney transplant. It is becoming increasingly evident that the persons in the burgeoning population with CKD are more likely to succumb to an adverse CVD outcome and die than reach the dialysis unit event free. Several aspects of this epidemic and the interplay between CKD and CVD were detailed in the symposium entitled "Cardiovascular Risk Factors and Chronic Kidney Disease."

Characteristics of CVD in Patients With CKD

Patients with CKD are faced with 3 distinct types of CVD, all of which are likely to lead to poor outcomes, noted Mark Sarnak, MD,^[2] of Boston, Massachusetts.^[3] These include left ventricular hypertrophy (LVH) with both eccentric and concentric variants prevalent in patients with CKD, atherosclerosis, and arteriosclerosis. Eccentric LVH is characterized by an increase in wall thickness that is in proportion to the increase in LV diameter and results from the pressure overload of fluid retention, anemia, or an arteriovenous fistula. Concentric LVH occurs when the growing thickness of the LV is greater than the changes in the LV diameter and is attributable to the hypertension typical of CKD and related aortic vessel stiffening. Atherosclerosis is the key element to occlusive vascular disease and ischemic heart disease. Atherosclerosis leads to luminal narrowing of both large and small coronary artery vessels, both of which contribute to the increased incidence of myocardial infarction observed in this population. The atherosclerotic process typical of this form of CVD is compounded in kidney disease by accelerated calcification, which is often observed in the plaques seen with this disease. Arteriosclerosis is a disease of large vessels such as the aorta and carotid arteries and is due to medial degeneration leading to loss of elasticity in and stiffness of the vessel.

Patients with CKD have a clustering and perhaps amplification of many of the traditional "Framingham" risk factors for CVD, but in addition suffer from a preponderance of nontraditional risk factors that are relatively unique to kidney disease. These include anemia, extracellular fluid excess, abnormal calcium/phosphate metabolism, hyperhomocysteinemia, increased oxidative stress, and inflammation, Dr. Sarnak pointed out. He acknowledged that this coalescence of risk factors is likely to account for a large degree of the excess CVD observed in this population. CKD as a distinct entity represents a previously under-recognized risk factor for CVD. Dr. Sarnak emphasized that diminished glomerular filtration rate as well as proteinuria, including microalbuminuria, are powerful predictors of CVD, especially in high-risk populations.

The Link Between CKD and CVD

Two emerging concepts help to explain the link between CKD and CVD. The lipid abnormalities that one observes in CKD patients were discussed by Florian Kronenberg, MD,^[4] of Innsbruck, Austria. When using the standard laboratory battery to assess lipids in patients with kidney disease, more often than not, one will have a difficult time identifying significant lipid abnormalities that account for the excess incidence of CVD in this population, noted Dr. Kronenberg. While there is a strong direct correlation between LDL cholesterol and the incidence of adverse CVD events in the general population, it has been observed that LDL levels are highly variable and not typically elevated in patients with kidney disease. Dr. Kronenberg explained that the usual method of estimating LDL cholesterol by subtracting HDL cholesterol and a fifth of triglycerides does not take into account lipid remnant particles and Lp(a), which are increased in kidney disease.^[5] The fractional catabolic rate of Lp(a) is decreased in hemodialysis patients with an increase in its residence time. Furthermore, the apo(a) phenotype was strongly associated with adverse events in patients on hemodialysis and may be an important marker of those at high risk for CVD. Elevations in Lp(a) and apo(a) are not treatable by statins, and when asked whether patients with kidney disease should have the routine lipid profile modified to include these putative lipoprotein particles, Dr. Kronenberg remarked that more work was needed to make measurement of these elements a part of routine practice.

Reactive Oxidative Species (ROS)

Toshimutsu Niwa, MD,^[6] of Nagoya, Japan, discussed the role of ROS in the development of CVD in patients with kidney disease. Excessive ROS is expressed in a milieu where the production of oxidants is greater than the local antioxidant reserve. The production of ROS in proximity to the vascular endothelium leads to oxidation of LDL, explained Dr. Niwa. Oxidized LDL particles are taken up by local macrophages, which transform into foam cells and lead to calcification of vessel walls. It is also suspected that in addition to oxidation of LDL, ROS can also induce several pathways in the endothelium, which promote atherosclerosis. ROS may inactivate nitric oxide and promote several pro-atherogenic events in the endothelium, including leukocyte adherence, platelet aggregation, and impaired vasorelaxation. There are several byproducts of oxidative stress, including malondialdehyde (MDA), which results from lipid peroxidation; advanced glycation end-products (AGE), which result from carbohydrate oxidation; and glutathionyl hemoglobin and advanced oxidation protein products (AOPP), which result from protein oxidation. Several of these byproducts, most notably MDA, AGE, and glutathionyl hemoglobin, are elevated in hemodialysis patients.^[7] Dr. Niwa emphasized the link between oxidative stress and inflammation suggesting that ROS stimulates inflammation, and further noted the significant correlation between MDA and C-reactive protein (CRP), in addition to an association between MDA, troponin T, and coronary calcium scores in hemodialysis patients.

There are several potential opportunities to reduce ROS in dialysis patients. These include treatment of infection; use of biocompatible dialysis membranes; control of hypertension, alterations in glucose metabolism, hyperlipidemia, and anemia; and avoidance of iron overload. In addition, there are several promising therapies that might be considered for reduction of ROS, including vitamin E-modified dialyzers, acetylcysteine treatment, and folic acid, which is currently being evaluated as a means to reduce homocysteine and the incidence of CVD events in renal transplant recipients.

Causes of Death in Patients With End-stage Renal Disease (ESRD)

Charles Herzog, MD,^[8] of Minneapolis, Minnesota, reviewed data from the United States Renal Data System (USRDS), pointing out that a large proportion of cardiac deaths in patients with ESRD are attributable to arrhythmias or sudden death. The increased incidence of arrhythmic events is related to ischemic episodes and remodeling observed with the LVH typical of kidney disease. While the overall death rate has decreased over the last several years in patients with ESRD, mortality rates and CVD event rates rise with increasing time on dialysis. Dr. Herzog concluded that dialysis should be considered "bad for your heart." He illustrated how there was some geographic variation in the incidence of CVD among dialysis patients in the United States and that this should be examined closely.

Improving Outcomes in Dialysis Patients

Biomarkers such as CRP and cardiac troponin T are valuable tools for identifying those dialysis patients at greatest risk for a cardiac event. Dr. Herzog posed the question, Can the risk of CVD be reduced in the dialysis population? Since sudden death accounts for a majority of cardiac death in this population, he suggested several means by which to reduce the incidence of this catastrophic event. First, he suggested that more "physiologic" dialysis prescriptions have the potential to reduce the occurrence of sudden death in this population, since typical dialysis regimens involve rapid fluid removal, electrolyte shifts, and hypotension. He stressed the importance of avoiding low potassium baths if possible, and emphasized the importance of mandating the presence of automatic external defibrillators in dialysis units since the critical element to recovery after cardiac arrest is rapid resuscitation. Dr. Herzog concluded by pointing out the importance of the implantable cardioverter defibrillator (ICD) in patients who are survivors of cardiac arrest or at high risk for such an event. He presented data from the USRDS demonstrating that survivors of a sudden cardiac arrest who have an ICD have a significantly better survival rate compared with survivors of cardiac arrest who do not have an ICD.^[9]

The overall message of the session was that CKD patients are stricken with an unacceptably high incidence of CVD. There is a growing body of work, which will assist in elucidating the mechanisms responsible for this lethal association and will point to useful therapies to improve the outcome of patients who suffer from kidney disease.

References

1. Foley RN, Parfrey PS, Sarnak MJ. Cardiovascular disease in chronic renal disease: clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32:S112-S119. Abstract
2. Sarnak M. Chronic kidney failure as a risk factor for cardiovascular disease. Program and abstracts from American Society of Nephrology Renal Week 2003; November 12-17, 2003; San Diego, California.
3. Sarnak, MJ. Cardiovascular complications in chronic kidney disease. Am J Kidney Dis. 2003;41:S11-S17. Abstract
4. Kronenberg F. Dyslipidemia. Program and abstracts from American Society of Nephrology Renal Week 2003; November 12-17, 2003; San Diego, California.
5. Trenkwalder F, Gruber A, Konig P, Dieplinger H, Kronenberg F. Increased plasma concentration of LDL-unbound apo(a) in patients with end-stage renal disease. Kidney Int. 1997;52:1685-1692. Abstract
6. Niwa T. Oxidative stress. Program and abstracts from American Society of Nephrology Renal Week 2003; November 12-17, 2003; San Diego, California.
7. Takayama F, Tsutsui S, Horie M, Shimokata K, Niwa T. Glutathionyl hemoglobin in uremic patients undergoing hemodialysis and CAPD. Kidney Int. 2001;78:5155-5158.
8. Herzog C. Sudden death in dialysis patients. Program and abstracts of American Society of Nephrology Renal Week 2003; November 12-17, 2003; San Diego, California.
9. Herzog CA. Cardiac arrest in dialysis patients: approaches to alter an abysmal outcome. Kidney Int. 2003;84:S197-S200.